Research done in vitro has shown that GLP-1 is mildly insulinomimetic in both fat and muscle. We undertook a study in non-obese (i.e. normal glucose uptake and therefore not resistant to insulin's actions ) subjects (published J. Clin. Endocrinol. Metab., 83:2399-2405,1998) with intravenous GLP-1 and could not demonstrate this phenomenon. We used state-of-the-art methodology using tritiated glucose to study glucose output and uptake by the liver. However, as the subjects were young with perfectly normal insulin action we may not have been able to show subtle insulinomimetic actions. We therefore initiated a study in obese, non diabetic (insulin resistant, with normal fasting blood glucose) subjects to see if GLP-1 would decrease resistance to insulin. We finished the study in 12 subjects whose BMI was >30. It does appear that GLP-1 is indeed insulinomimetic (i.e. augments insulin action) in obese people (ms submitted). It also appears to suppress formation of non-esterified fatty acids-more than does insulin alone. This tells us that a GLP-1 like compound, such as GLP-1 itself or exendin-4, might not only be useful in diabetes, but also in glucose intolerance. Treatment options that are presently available for type 2 diabetes are less than perfect. The vast majority of type 2 diabetic subjects require insulin at some point in their lives because of deteriorating beta cell function. Project Number Z01AG00214-08 LCI has shown that continuous GLP-1 treatment improves glucose tolerance and increases the rate of beta cell turnover in rodents. GLP-1, given subcutaneously to humans before each meal, does lower blood sugar. But blood sugar levels rise again before the next bolus. We wished to see if GLP-1 given continuously subcutaneously would normalize and maintain a normal blood sugar. We therefore gave GLP-1 continuously subcutaneously, via a Mini-Med pump (a small pump about the size of a beeper) to Type 2 diabetic subjects for 48 hours. We then examined glucose homeostasis by reviewing insulin secretory capacity and insulin sensitivity. Data from 5 subjects showed that GLP-1 given in this manner can normalize blood sugars. We then expanded on our findings to the actual patient. Using diabetic patients who are admitted to hospital with an acute stroke and who are also suffering from diabetes we have initiated a project whereby GLP-1 is given intravenously for the first 72 h of their hospital stay (IRB number: HRV99-08-13-01). In this manner we will be able ascertain if GLP-1 can normalize blood glucose not only in an out-patient setting by also under stressful conditions.